Compositions for liquefaction of respiratory secretions



United States Patent COMPOSITIONS FOR LIQUEFACTION OF RESPRATORY SECRETIONS Joseph B. Miller, Mobile, Ala.

No Drawing. Application February 28, 1956 Serial No. 568,169

Claims. (Cl. 167-58) This invention relates to aqueous preparations nebulizable to aerosol form for use in the alleviation of pul monary obstruction caused by secretions in the respiratory tract.

It is an object of this invention to provide compositions which can be employed in inhalation therapy for respiratory conditions involving airway obstruction caused by retained secretions. It is a particular object of my invention to provide compositions which can be employed to dissolve, loosen, or liquefy bronchopulmonary exudates and transudates.

In recent years, the availability of new antibacterial agents has remarkably reduced the dangers of respiratory infections, but bronchial obstruction due to accumulation of obstructive exudates remains a serious medical problem. Obstructive exudates are present in a wide variety of bronchopulmonary conditions. Thus, viscid exudates are usually present in asthma, tuberculosis, bronchitis, brouchiectasis, laryngotracheobronchitis, bronchiolitis, bronchial pneumonia, allergic bronchopneumonia, pertussis, and diphtheria. In poliomyelitis or encephalitis, there may be diaphragmatic or intercostal paralysis with resultant weakness or loss of cough reflex, followed by accumulation of thickened respiratory secretions. Such secretions also accompay general anesthesia, thoracic surgery, the use of endotracheal catheters for anesthesia, bronchoscopy, tracheotomy, inhalation of irritant gases or dust, and aspiration of foreign material such as gastric contents, meconium or amniotic fluid.

In the bronchopulmonary conditions mentioned above, there is an outpouring of mucus of mucopurulent exudate, and in addition there may be edema and bronchospasm, which further encroach on the bronchial lumen. The secretions tend to dry out and become more viscid because of the low relative humidity of the inhaled air and the relative increase in velocity of the air current of inhalation due to hyperpnea and to the narrowing of the bronchial passageway. In the presence of local inflammation, ciliary action breaks down; and, when generalized toxicity occurs the cough reflex is diminshed or lost. As a consequence, the patient is in immlnent danger of bronchial obstruction, and he may asphyxiate or drown in his own secretions. Thus, the chief danger of retained secretions is airway obstruction. The obstruction may occur in a lobule, segment, lobe or entire lung and may result in asphyxia, atelectasis, emphysema, or infection and fibrosis behind the obstruction. All of these sequelae are troublesome and, in children, often fatal, hence the importance of liquefying and removing secretions before the occurrence of airway obstruction and its potential complications.

Conventional humidity therapy, such as the use of steam humidification or nebulization of water in cooled tents, does not actively dissolve viscid bronchopulmonary secretions and instead merely slows down the drying out of the secretions. If the recuperative powers of the patient are adequate, and he receives whatever supportive and specific measures are indicated, he may recover. In

many cases, however, water vapor alone does not work rapidly or effectively enough to prevent obstructive complications or to save life.

In accordance with the present invention, I have now succeeded in preparing aqueous compositions nebulizable to an aerosol form which, when breathed by a patient afflicted with one Or more of the bronchopuhnonary conditions mentioned hereinabove, liquefy mucous, serous, and purulent bronchopulmonary exudates, thus tending to relieve and prevent respiratory obstruction in the patient by facilitating expectoration, suctioning out, or absorption of the secretion. My new compositions consist of an aqueous solution nebulizable to an aerosol and comprising a small percentage of an alkylaryl polyether alcohol, a droplet stabilizing agent such as glycerol or similar polyhydroxy alcohol, and an alkaline buffer to bring the solution to pH 8.0-8.5.

The alkylaryl polyether alcohols useful in practicing my invention are the surface-active wetting and penetrating agents described in Us. Patent 2,454,541, issued November 23, 1948, which are oxyethylated alkylphenolformaldehyde polymers prepared by condensing an alkylphenol with 0. -1.0 mole of formaldehyde and then reacting the product thus obtained with 8-60 moles of ethylene oxide. Particularly useful alkylaryl polyether alcohols for the purposes of my invention are the oxyethylated p-tertiary octylphenol-formaldehyde polymers produced by condensing approximately equimolar amounts of p-tertiary octylphenol and formaldehyde and then reacting the product with 10-20 moles of ethylene oxide. A preferred compound of this group is the product con taining ten ether groups per p-tertiary octylphenol nucleus Which is known under the name Superinone and also under the designation Triton WR-1339; the preparation of a closely similar and equivalently useful compound is described in Example 1 of US. Patent 2,454,541, wherein eleven moles of ethylene oxide are used.

The alkylaryl polyether alcohol is used in relatively small amount in my compositions. Ordinarily, 0.025% to 2.5% by weight of the alkylaryl polyether alcohol in the aqueous preparation is sufficient for satisfactory results. For general use, I have found that about 01-02% by Weight of the alkylaryl polyether alcohol is preferable, although in particular circumstances higher or lower percentages may be more useful. Thus, where the exudates in the respiratory tract are especially thick or copious, for example, I prefer to use a higher percentage of the alkylaryl polyether alcohol, for instance up to about 2.5

The droplet stabilizing agent, such as glycerol, propylene glycol, or a similar polyhydroxy alcohol, results in the production of an aerosol mist, when the aqueous preparation is nebulized, which is of significantly longer duration than when the droplet stabilizing agent is not present. The stabilized droplets maintain their integrity and this permits their inhalation into the air space of the bronchial tree. The amount of the droplet stabilizing agent can be varied somewhat according to the dropletlife desired but ordinarily it sufiicesto employ about 0.05-10% by Weight of the glycerol or similar agent. Generally speaking, increasing the amount of the alkylaryl polyether alcohol in my compositions permits a decrease in the amount of glycerol required to produce a given degree of droplet stability.

The alkaline buffer is conveniently and preferably an alkali metal bicarbonate such as sodium or potassium bicarbonate. However, if desired, there can be used other agents such as sodium acid phosphate titrated with sodium hydroxide until the resulting mixture has the appropriate pH, that is about 8.0-8.5. Usually, I have found that about 1-2% of an alkali metal bicarbonate by Weight is satisfactory.

Because of the presence of the wetting agent in my preparations, they have a tendency to foam, but this property does not ordinarily cause any appreciable difficulty with the preparation and handling of them. Moreover, if desired the tendency to foam can be reduced or substantially prevented in my new aqueous preparations iby dispersing lther-ein a small amount of a silicone as an antifoam agent. The silicones are of course characterized by a very low order :of toxicity and for this reason are especially well suited to use in the compositions of (the present invention. It has been determined that "the :silicone 'does not interfere with effectiveness and safety of my preparations in the treatment of pulmonary obstruction; to the contrary, 'the use of these compositions :may :afford particular advantage for the treatment of respiratory conditions wherein tracheal foam is contributory to :airway obstruction, as for example in pulmonary edema, and both mucolytic and foam-collapsing action are desired.

As will be appreciated, the amount of silicone needed to impart the desired antifoaming property to :my compositions varies somewhat with the amount of alkylaryl polyether alcohol present but, for any given percentage of alkylaryl polyether alcohol, only a small relative amount of the siliconeis required for satisfactory results. Thus, it is usually sufficient for substantial inhibition of foaming to employ the silicone in the amount of about 10-200 parts per million (p.p.m.) in the aqueous compositionwhen ;025'2.S% of the wetting agent is used, the quantity of silicone used being increased as the percentage of wetting agent employed is increased. How- 'ever, on the one hand, some diminution of foaming is obtained even when the concentration of the silicone is 'as low as l p.p.m., and on "the other hand I have found that the very low toxicity of the silicones permits the -use of larger amounts of the silicone'in my compositions, for instance up to several thousand p.p.m., if desired.

As understood in the art, the term silicone refers to organopolysiloxanes having the formula and their polymers, where R and R are the same or different alkyl, aryl, or cycloaliphatic radicals. In general, the organic polysiloxanes where R and R are lower alkyl radicals having 1-5 carbon atoms, the methyl radi- "cal being preferred, have been found to be most valuable for use as antifoaming agents-in the compositions of the instant invention; these compounds, known as methylpolysiloxanes, are available in-an almost continuous series of molecular sizes from lower members such as hexamethyldisiloxane and dodecamethylpentasiloxane to higher members containing 1000 or more silicon atoms per molecule, the viscosity of the members increasing f1'01110i65 centistoke at 25 C. for hexamethyldisiloxane to very large values for the grease-like higher molecular weight compounds. A readily available and useful silicone for use in my preparations is the high molecular weight methylpolysiloxane having a viscosity of 30,000 centistokes which is marketed under the designation Antifoam A as a grease-like product having dispersed 'therein as a filler 5% of silicon dioxide with a particle size of .less than 0.05micron. However, the lower molecular weight methylpolysiloxanes can be used if desired.

The silicone, which isof course water'insoluble, is incorporated into my aqueous compositions most conveniently by adding-it in the form of an oil-in-water type of emulsion, since uniform dispersion is thereby facilitated. For this purpose, a water-soluble emulsifying agent, such .as a polyoxyethylene ester, for example a polyoxyethylenemono-ester of a higher fatty acid, is preferred, although other emulsifying agents can be employed -if desired.

The new compositions .of my invention are administered by atomizing or, preferably, nebulizing the solution in conventional manner-so that the aerosol mist thus produced is breathed by the patient. In many cases the patient must for best results be exposed to the aerosol mist for at least four to twenty-four hours, and in some instances for two or three days or more. Thus, it is frequently most convenientto place the patient in an oxygen tent or, in the case of an infant, in an incubator and nebulize the solution in the tent or incubator by means of a nebulizer in which the supply of the solution can be continuously replenished, as by dripping the fluid into the nebulizer from a 'clysis bottle. However, in other instances where it is desired to treat the patient with the aerosol mist for short periods of fifteen to twenty minutes every day or every several hours, a conventional nebulizer of small capacity, such as a De Vilbiss No. 40 *nebu'lizer, affords the most convenient means :of adminis- 'tration.

Optimum results .are produced when the 'nebuliZer produces a mist of the solution in which the range ;of particlesi-ze is about 0.5 to 3 micra. However, droplets 'oflarger size are eifectivein affording the advantages 'of my invention and the chief disadvantage of the use of thelarger size droplets is greater deposition of the .droplets before entering deeply into the respiratory passages of the patient, thus leading to wastage-ofthesolution.

Depending on a great number of factors, such as :the length of time of treatment-and the size of the droplets employed, the volume of the solution whichzis'nebulized in a given case may fall-within alrather wide .range, for example from a few cubic centimeters up to :a liter or more. For example, :I found that when :air or :oxygen;:is passed through a given inebulizer at a rate of about'eight liters perminu'te,approximately 500 cc..of solution were rnebulized each twenty-four hours; using a diiferent inebulizer and the same rate of flow, the 500cc. of solution may lastonly six or sevenhours.

The clinical use of my new compositions inraerosol therapy has afforded successfulresults, without untoward side etfects,-in the treatment of bronchopulmonary exudates associated with fibrocystic disease, spasmodic croup, pulmonary phthisis, asthmatic bronchitis, chronic "bronchitis, bronchiectasis, bronchiolitis, bronchopneumon'ia, virus pneumonia, tracheotomy, pertussis, :foreign body in the bronchi,=diphtheria,. encephalitis with-retained secretions, pulmonary edema, and mucous obstructions :in-the newborn.

"It will be appreciated that my new preparationsare primarily designedto afford relief and prevention .ofpre- 'spiratory obstruction, and when employed aloneas described above are not intended to replace .other therapeutic measures where theseareindicated. :Rather, the function x of :my composition ,is to keep the .patient alive and unobstructed until the other therapeutic :measures have time to take effect.

My-compositions may also be used as vehicles for drugs.

The .preparationof compositions inraccordance with my invention is illustrated by :the .following examples "without, however being restricted thereto.

Example 1 1.25 g. :of .oxyethylated ;p-.tertiary .octylphenol-formal- :dehyde rpolymer (Superinone) prepared ,in accordance with the operative procedure described in Example 1 oflU'.S. Patent 2,454,541 and containing tenether groups per p-tertiary octylphenolinucleus, 50.00 g. of glycerol, :and 20.00 g. of sodium bicarbonate were dissolved in sufiicient water to make.l000 cc. of solution. The solu- =tionthus obtained .was filtered, placed in a closed container, :andsterilized byautoclaving at 121 C.;for fifteen minutes. The sterilized solution was :milky when hot -butbecamesclear-onrzcooling. This preparation contained "approximately I 0.125 of oxyethylated ;p:tcrtiary aoctylphenol-formaldehyde polymer, 5% of glycerol, and 2% of sodium bicarbonate. The pH of the solution was approximately 8.2. In other instances, the sterilization of the solution was effected by passing it through a bacterial filter.

This preparation, which represents a preferred embodiment of my invention, was found to be highly useful in inhalation therapy, in both children and adults, for eliminating bronchial obstructions caused by viscid secretions in asthma, sinusitis, bronchitis, and bronchiectasis, for example.

Example 2 Following the same procedure described above in Example 1, but employing 12.50 g. of the oxycthylated ptertiary octylphenolformaldehyde polymer and 0.5 g. of glycerol, there was obtained a preparation containing approximately 1.25% of this ingredient, 0.05% of glycerol and 2% of sodium bicarbonate.

This preparation was found to be particularly useful for treatment of severe forms of respiratory obstruction where the exudates involved were especially thick and copious.

Example 3 A. 125 g. of oxycthylated p-tertiary octylphenol-formaldehyde polymer (Superinone) and 5000 g. of glyercol were mixed thoroughly and to this mixture was added 5 liters of water. The resulting solution was mixed with an aqueous solution containing 1000 g. of potassium bicarbonate, and the mixture was diluted with water to bring the volume of the solution to 98 liters. This solution was sterilized by filtration. This preparation is useful as such but if desired can be rendered resistant to foaming as described below.

B. 10.0 g. of a high molecular weight methylpolysiloxane having a viscosity of 30,000 centistokes thickened to grease-like consistency by addition of 5% of a noncrystalline form of silica in the colloidal state (available commercially as DC Antifoam A, manufactured by the Dow Chemical Company) was added to a solution of 10.0 g. of polyoxyethylene 40 monostearate having the formula H(OCH CH ),,OCOC H CH where n is approximately 40 (polyoxyl 4O stearate, The United States Pharmacopoea, XV, 1955, pp. 565-566) in 80 ml. of water. The resulting mixture was blended thoroughly and then added, with stirring, to 1900 ml. of water. This solution was sterilized by autoclaving, allowed to stand at room temperature for twenty-four hours, and filtered aseptically through a coarse glass frit to remove a considerably quantity of coagulated and undispersed silicone. Analysis of the filtrate showed that it contained approximately 1250 parts of silicone per million parts of the dispersion. (Analysis of each dispersion prepared is necessary if it is desired to adjust the silicone concentration in the final preparation to a particular predetermined approximate value.) 10.0 ml. of the silicone dispersion obtained in this manner was mixed with 490 ml. of the aqeous preparation obtained above in part A, using aseptic technique, thereby yielding an aqueous preparation containing the silicone in the amount of about 25 parts per million.

This preparation, which was highly resistant to foaming, was found to be highly useful in the treatment of bronchial obstruction when foam was one of the obstructing materials, as in pulmonary edema.

C. By adding 40.0 ml. of the silicone dispersion obtained as described above in part B to 460 ml. of an aqueous preparation obtained as described above in part A except that the solution had been diluted to 92 liters rather than 98 liters there was obtained a composition containing approximately 0.125 of oxyethylated ptertiary octylphenol-formaldehyde polymer, 5% of glycerol, 1% of potassium bicarbonate and 100 parts per million of the silicone. This composition, which was highly resistant to foaming, was found to be highly useful in the treatment of bronchial obstruction when foam was a contributory factor in the obstruction.

In all of the above examples, there can be used equivalently, instead of the Superinone, any of the related oxyethylated p-tertiary octylphenol-formaldehyde polymers containing 10-20 ether groups per p-tertiary octylphenol nucleus as described in the aforementioned U.S. Patent 2,454,541.

This application is a continuation-in-part of my copending application Serial No. 337,877, filed February 19, 1953, now abandoned.

I claim:

1. A composition neublizable to an aerosol for liquefying respiratory exudates to aid in their removal consisting essentially of an antibiotic-free aqueous solution of 0.025-2.5% of oxycthylated p-tertiary octylphenol-formaldehyde polymer, 0.05-10% of glycerol, 1-2% of an alkali metal bicarbonate, and the balance Water.

2. A composition nebulizable to an aerosol for liquefying respiratory exudates to aid in their removal consisting essentially of an antibiotic-free aqueous solution of approximately 0.125% of oxycthylated p-tertiary octylphenol-formaldehyde polymer, approximately 5% of glycerol, approximately 2% of sodium bicarbonate, and the balance water.

3. A composition neublizable to an aerosol for liquefying respiratory exudates to aid in their removal consisting essentially of an antibiotic-free aqueous solution of approximately 1.25 of oxycthylated p-tertiary octylphenol formaldehyde polymer, approximately 0.05 of glycerol, approximately 2% of sodium bicarbonate, and the balance Water.

4. A composition nebulizable to an aerosol for liquefying respiratory exudates to aid in their removal consisting essentially of an antibiotic-free aqueous solution of approximately 0.125% of oxycthylated p-tertiary octylphenol-formaldehyde polymer, approximately 5% of glycerol, approximately 1% of potassium bicarbonate, a small amount of a methylpolysiloxane dispersed in said composition as an antifoam agent, and the balance water.

5. A composition neublizable to an aerosol for liquefying respiratory exudates to aid in their removal consisting essentially of an antibiotic-free aqueous solution of 0.025-2.5% of oxycthylated p-tertiary octylphenol-formaldehyde polymer, 0.05-10% of glycerol, l-2% of an alkali metal bicarbonate, a small amount of a methylpolysiloxane dispersed in said composition as an antifoam agent, and the balance water.

Miller et al.: Am. J. of Diseases of Children, August 1950, vol. 80, pp. 207-237.

Ravenel: J.A.M.A., February 28, 1953, vol. 151, pp. 707-711.

Ross: Chemical Industries, May 1949, pp. 757-759. 

1. A COMPOSITION NEUBLIZABLE TO AN AEROSOL FOR LIQUEFYING RESPIRATORY EXUDATES TO AID IN THEIR REMOVAL CONSISTING ESSENTIALLY OF AN ANTIBIOTIC-FREE AQUEOUS SOLUTION OF 0.025-2.5% OF OXYCTHYLATED P-TERTIARY OCTYLPHENOL-FORMALDEHYDE POLYMER, 0.05-10% OF GLYCEROL, 1-2% OF AN ALKALI METAL BICARBONATE, AND THE BALANCE WATER 